Bidirectional interactions between indomethacin and the murine intestinal microbiota

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Abstract

The vertebrate gut microbiota have been implicated in the metabolism of xenobiotic compounds, motivating studies of microbe-driven metabolism of clinically important drugs. Here we studied interactions between the microbiota and indomethacin, a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenases (COX) -1 and -2. Indomethacin was tested in both acute and chronic exposure models in mice at clinically relevant doses, which suppressed production of COX-1 and COX-2 derived prostaglandins and caused small intestinal (SI) damage. Deep sequencing analysis showed that indomethacin exposure was associated with alterations in the structure of the intestinal microbiota in both dosing models. Perturbation of the intestinal microbiome by antibiotic treatment altered indomethacin pharmacokinetics and pharmacodynamics, which is likely the result of reduced bacterial β-glucuronidase activity. Humans show considerable inter-individual differences in their microbiota and their responses to indomethacin - thus the drug-microbe interactions described here provide candidate mediators of individualized drug responses.

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Xue Liang

Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, Univ. of Pennsylvania, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Kyle Bittinger

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Xuanwen Li

Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Darrell R Abernethy

Office of Clinical Pharmacology, Food and Drug Administration, Silver Spring, United States

Competing interests
The authors declare that no competing interests exist.
Frederic D Bushman

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Garret A FitzGerald

Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

For correspondence
garret@upenn.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#803903) of the University of Pennsylvania. Throughout the study, every effort was made to minimize suffering.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.